Age-related macular degeneration (AMD) is the most common cause of acquired visual impairment in people over the age 60. AMD is a multifactorial, complex disorder associated both with environmental and genetic factors. Currently, no reliable treatment options are available for AMD with the exception of the laser photocoagulation therapy that can be applied to a small fraction of patients with short-term effects. Despite concerted efforts over the last several years, the general knowledge of genetic determinants of AMD has not advanced substantially. The underlying hypothesis of this proposal is that increased susceptibility to AMD in individual cases results from a combination of subtle defects in many genes, i.e., from specific genotype(s). This proposal suggests a continuation of our current program directed towards deciphering the genetic cause of AMD by a combination of several approaches. These include: 1) Completing large, clinically and genetically well-characterized, cohorts of AMD patients and matched controls ((2000 samples each); 2) Utilizing high-throughput screening methods, including recently introduced in our laboratory genotyping microarrays, to obtain data on genetic heterogeneity in these populations; 3) Correlating the large numbers (>4 millions) of derived genotypes with specific (endo-) phenotypes in AMD by statistical analyses; 4) Developing animal models to further define AMD-associated candidate genes in functional pathways and to determine the functional relevance of genetic studies. Our progress and experience in this field of research suggests that a successful project should include all the components listed above. Identification of genes, alleles, haplotypes, and genotypes underlying the AMD complex trait and understanding how these defects contribute to the development of macular degeneration has the potential to improve the quality of life of the affected individuals. Further, it will enable the accurate identification of at-risk individuals before they develop the disorder, and has the potential to modify or prevent the devastating visual consequences of this disorder in future generations. [unreadable] [unreadable]